Bowel diseases are diseases with abnormal condition of small intestine or large intestine, which are accompanied with major symptoms including diarrhea (bacterial and viral infectious diarrhea, diarrhea caused by inflammatory bowel diseases, irritable bowel syndrome, or drug-induced enteritis and the like), constipation, or mucous bloody stool or the like. Among them, inflammatory bowel disease including ulcerative colitis (UC) and Crohn's disease (CD) is a chronic nonspecific inflammatory disease of the bowel which is frequently observed in Western countries, and the number of patients with the disease has been rapidly increasing also in Japan. Although a cause of the inflammatory bowel disease has not yet been identified, it is considered that the onset of the disease involves complicated participations of genetic, immunologic, and environmental medicinal factors.
For treatment of Crohn's disease, in order to control abnormally activated immunological reactions, nutrition therapy is generally applied to reduce exposure to food antigen which causes a stress to gastrointestinal tract. However, because the nutrition therapy alone is not expected to be effective for ulcerative colitis, an adrenal corticosteroid such as prednisolone is administered. As drug therapies, 5-aminosalicylic acid (tradename: Pentasa) and salazosulfapyridine (tradename; Salazopyrin), which are known to suppress inflammation-inducing substances (inflammatory cytokines, leukotriene, active oxygens and the like), have been generally used, and for patients with severer symptoms than moderate, adrenal corticosteroids (tradename; Prednisolone, Rinderon, and the like), cyclosporine (tradename: Sandimmune) and FK506 (tradename: Prograf) as immunosuppressant agents have been used. However, no medicament has been developed which exhibits remarkable effectiveness against inflammatory bowel disease or has reduced adverse effects.
Retinoic acid (vitamin A acid), an active metabolite of vitamin A, has extremely important physiological functions, e.g., inducing differentiation of immature cells under development processes toward mature cells having specific functions, acceleration of cell proliferation, and life support action. It has been revealed that various vitamin A derivatives synthesized so far also have similar physiological functions, for example, the benzoic acid derivatives disclosed in Japanese Patent Unexamined Publication (KOKAI) Nos. (Sho)61-22047/1986 and (Sho)61-76440/1986, and the compounds described in Journal of Medicinal Chemistry, 1988, Vol. 31, No. 11, p. 2182. “Retinoids” is a general term for retinoic acid and the aforementioned compounds having retinoic acid-like biological activities.
For example, it was proved that all-trans retinoic acid binds as a ligand to the retinoic acid receptor (RAR) present in cellular nucleus, which belongs to the intranuclear receptor super family (Evans, R. M., Science, 240, p. 889, 1988), and regulates proliferation and differentiation of animal cells or cellular mortalities (Petkovich, M., et al., Nature, 330, pp. 444-450, 1987). In addition, as for the expression of physiological activities of retinoic acid, the existence of retinoid X receptor (RXR of which ligand is 9-cis-retinoic acid) has been elucidated. The retinoid X receptor has been revealed to control the expression of the physiological activities of the retinoic acid by inducing or suppressing the transcription of a target gene by forming a dimer between the retinoic acid receptor (RAR) (Mangelsdorf, D. J. et al., Nature, 345, pp. 224-229).
It has also been suggested that the aforementioned compounds having the retinoic acid-like biological activities, e.g., 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoic acid: Am80, also bind to RAR in similar manners to retinoic acid to exhibit their physiological actions (see, Hashimoto, Y., Cell Struct. Funct., 16, pp. 113-123, 1991; Hashimoto, Y, et al., Biochem. Biophys. Res. Commun., 166, pp. 1300-1307, 1990). Clinically, these compounds were found to be useful for therapeutic and preventive treatments of vitamin A deficiency disease, hyperkeratosis of epithelial tissue, rheumatism, delayed allergy, bone diseases, leukemia and certain types of cancer.
As for a relation between retinoids and bowel diseases such as inflammatory bowel disease, a supply of Vitamin A to patients with Crohn's disease was studied. However, the study was reported to be ineffective (Gastroenterology, 88, pp. 512-514, 1985). Drug therapies by using retinoids have been applied for psoriasis and acute promyelocytic leukemia (APL), and several clinical cases were reported in which all-trans retinoic acid or analogues thereof was administered to the patients who were also suffering from Crohn's disease. However, effectiveness of retinoids against Crohn's disease was not clarified (The Journal of the American Medical Association (JAMA), 252, pp. 2463, 1984; Arch. Dermatol., 124, pp. 325-326, 1988; Br. J. Dermatol., 123, pp. 653-655, 1990; Cancer Invest., 18, p. 98, 2000).